Synthesis of 4-aminoxanthones by an uncatalyzed, multicomponent reaction

Article abstract of DOI:10.1002/adsc.201300750

The synthesis of xanthones via a multicomponent reaction of isocyanides is described for the first time. In this one-pot process, a tandem [4+1] plus [4+2] cycloaddition leads to polysubstituted 4-aminoxanthones in excellent to quantitative yields at room temperature in a non-catalyzed reaction.

Full text of DOI:10.1002/adsc.201300750

COMMUNICATIONS
DOI: 10.1002/adsc.201300750
Synthesis of 4-Aminoxanthones by an Uncatalyzed,
Multicomponent Reaction
Ana Bornadiego,a Jesffls Díaz,a and Carlos F. Marcosa,*
a
Lab. Química Orgµnica y Bioorgµnica (L.O.B.O.), D. Química Orgµnica e Inorgµnica, Facultad de Veterinaria,
Universidad de Extremadura, 10071 Cµceres, Spain
Fax : (+34)-9-2725-7110; phone: (+34)-9-2725-7158; e-mail: cfernan@unex.es
Received: August 18, 2013; Revised: November 22, 2013; Published online: February 2, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300750.
Abstract: The synthesis of xanthones via a multi-
component reaction of isocyanides is described for
the first time. In this one-pot process, a tandem
[4+1] plus [4+2] cycloaddition leads to polysubsti-
tuted 4-aminoxanthones in excellent to quantitative
yields at room temperature in a non-catalyzed reac-
tion.
Not less importantly, aminoxanthones have also found
utility as fluorescent molecular probes for bio-
AHCTUNGTRENNUNG
imaging.[6a]
Despite this interest, only few syntheses of amino-
xanthones have been reported in the literature. With
the exception of a recently described base-promoted
addition of acetonitriles to 3-(1-alkynyl)chromones,[7]
aminoxanthones are generally obtained through indi-
rect procedures based on the reduction of nitroxan-
thones.[8] These are in turn obtained by classical syn-
thesis relying on the cyclization of either benzophe-
nones or diaryl ethers.[9] These multistep synthetic
procedures often involve harsh reaction conditions
and the use of strong acids or transition metals. Con-
sequently, the development of direct and efficient
À
Keywords: biological activity; C C bond formation;
cycloaddition; Diels–Alder reaction; heterocycles;
multicomponent reactions
Xanthones are a family of secondary metabolites, nat- routes to aminoxanthones is highly desirable.
urally occurring in higher plants, fungi, lichens and Multicomponent (MCR) reactions are highly con-
bacteria. Many natural and synthetic xanthones are vergent processes characterized by the formation of
able to interact with diverse biological targets, and several bonds in a single operation. The experimental
are therefore privileged structures in drug design.[1] simplicity and wide functional group tolerance of
Remarkably, xanthones containing H-bond donating/ MCRs[10] make this type of process a very attractive
accepting substituents, such as hydroxyxanthones, alternative for the synthesis of xanthones.
have shown to be effective inhibitors of monoamine
In the last years, we have designed new MCRs of
oxidase (MAO)[2] and different kinases,[3] and to inter- isocyanides for the synthesis of chromone deriva-
fere in the cell cycle.[4] Accordingly, hydroxyxanthone tives.[11] In a recent work we have also developed
derivatives have been proposed as valuable candi- a one-pot synthesis of anilines through a tandem
dates for the development of anti-tumoural and anti- [4+1]–[4+2] process, starting from a,b-unsaturated
inflamatory drugs.
The less explored aminoxanthones are especially in- the presence of catalytic Y
teresting, as they can be considered analogues of bio- We envisaged that 4-aminoxanthones (1) could be
carbonyl compounds, isocyanides and dienophiles in
AHCTUNGTRENNUNG
logically active hydroxyxanthones with, in some ways, readily prepared, using a similar strategy, by a Diels–
superior pharmacodynamic and pharmacokinetic Alder cycloaddition of dienophiles (3) with 3-amino-
properties.[5] Protonation of the amino group may 9H-furo
ACTHNUGRTENUNG[3,4-b]chromen-9-ones (4). These, in turn,
allow the interaction with negatively charged sites in could be obtained in situ by the [4+1] cycloaddition
the protein target, or the accumulation in certain tis- of isocyanides (6) with electron-deficient 3-carbonyl-
sues or cell structures.[5b] Furthermore, aminoxan- chromones (5; Scheme 1). This latter transformation
thones are key intermediates in the synthesis of would be predictably facilitated by the presence of
heteroACHTUNGTRENNUNG
cyclic fused xanthones,[5b,6] which have been strong electron-withdrawing groups on the starting
proposed as novel chemotherapeutic agents able to carbonylchromones (5). Here we describe the applica-
overcome adverse multidrug resistance (MDR).[6c] tion of this methodology for the efficient and straight-
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Synthesis of 4-Aminoxanthones
structure of this compound as the expected 4-amino-
xanthone 1a. The presence of a highly conjugated
push-pull system configured by the oxygen and amino
donor groups and the four electron-withdrawing car-
bonyls results in the product showing an intense fluo-
rescence.
Interestingly, the rate of the reaction was found to
be significantly benefited by a moderate increase in
the temperature. The solvent was also an important
factor. Thus, excellent yields were obtained both in
THF and toluene (Table 1, entries 2 and 4), though
considerably longer reaction times were required in
this latter solvent. Conversely, the reaction in CH2Cl2
is characterized by both lower yields and longer reac-
tion times (Table 1, entry 3). Successfully, after some
optimizations we were able to obtain quantitative
yields of 1a using equimolar amounts of the three
starting reagents at 358C in THF.
To explore the scope of this reaction, chromone 5a
was treated with N-phenylmaleimide (3a) and differ-
Scheme 1. Proposed retrosynthesis of 4-aminoxanthones.
forward synthesis of diversified amino-substituted ent isocyanides (6) in the optimized reaction condi-
xanthones. tions (Table 1). Both aliphatic and aromatic isocya-
Thus, we investigated the reaction of methyl 2-oxo- nides give the expected aminoxanthones in good to
2-(4-oxo-4H-chromen-2-yl)acetate (5a)[13] with cyclo- excellent yields. Unsurprisingly, a higher reaction rate
hexyl isocyanide (6a) and N-phenylmaleimide (3a) is observed with less hindered isocyanides (Table 1,
under different conditions. When the reaction was entries 8 and 9).
performed in THF at room temperature, a highly
To further extend the scope of this tandem proce-
fluorescent product began to precipitate from the re- dure, we decided to investigate the use of differently
ACHTUNGTRENNUNG
action medium after a few hours. Monitoring the re- substituted 3-carbonylchromones (5). Methyl 2-oxo-2-
action by TLC showed a slow transformation of the (4-oxo-4H-chromen-2-yl)acetate (5a) was readily ob-
starting chromone into this new product. Isolation by tained by the reaction of 3-(dimethylamino)-1-(2-hy-
simple filtration and characterization by the usual droxyphenyl)propen-1-one (9a) with methyl 2-chloro-
spectroscopic techniques successfully confirmed the 2-oxoacetate (10) and pyridine, as recently reported
Table 1. Optimization and scope of the reaction with different isocyanides.
Entry
R4
Solvent
Temperature [8C]
Time [h]
1 (Yield [%])[a]
1
2
3
4
5
6
7
8
9
10
c-C6H11
c-C6H11
c-C6H11
c-C6H11
t-Bu
2,6-Me2C6H3
PHCH2
C5H11
4-MeOC6H4
CH2CO2-t-Bu
THF
THF
DCM
toluene
THF
THF
THF
THF
THF
THF
25
35
35
35
35
35
35
35
35
35
24
96
IR[b]
1a (99)
1a (84)
1a (97)
1b (93)
1c (67)
1d (93)
1e (97)
1f (99)
1g (82)
120
144
96
144
78
22
22
49
[a]
General procedure: 1.1 equiv. of isocyanide and 1.1 equiv. of dienophile were added under nitrogen to a solution of
1 equiv. of chromenone in the specified solvent.
IR=incomplete reaction.
[b]
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Table 2. Synthesis of 2-oxo-2-(4-oxo-4H-chromen-3-yl)acetates (5).
Entry
R1
R2
R3
Time [min]
Enaminone 9[a] (Yield [%])
Time [min]
Chromone 5[b] (Yield [%])
1
2
3
4
5
H
H
H
H
H
H
Cl
Me
H
OMe
H
H
H
2
1
1
1
1
9a (89)
9b (86)
9c (85)
9d (93)
9e (91)
7
14
7
10
20
5a (85)
5b (67)
5c (81)
5d (78)
5e (30)
benzo
[a]
General procedure for the synthesis of enaminones (9a–9e): ortho-hydroxyacetophenone 7a–e (10 mmol) and dimethylfor-
mamide dimethyl acetal (10 mmol) were irradiated in a microwave reactor for 1–2 min at 1508C.
General procedure for the synthesis of chromenones (5a–5e): a solution of methyl chlorooxoacetate (1.65 mmol), enami-
none 9a–9e (1.5 mmol) and pyridine (3.3 mmol) in 1,2-dichloroethane (1 mL) was irradiated in a microwave reactor for
7–20 min at 1008C.
[b]
by Iaroshenko and Langer.[13] Our modification of
Finally, the reaction has also been performed with
this procedure, using microwave irradiation, affords different dipolarophiles. N-phenyl- (3a) and N-meth-
a good yield of 5a in only 10 min, rather than the 8 h ylmaleimide (3b), maleimide (3c), and maleic anhy-
required in the original procedure. Analogously, other dride (3d) were reacted with diverse chromones (5)
carbonylchromones (5a–e; Table 2) were conveniently and isocyanides (6), affording the corresponding prod-
prepared starting from enaminones containing differ- ucts (1) in moderate to excellent yields (Table 3, en-
ent substituents (9a–e).
tries 6–14). In the less favourable case, electron-poor
These enaminones (9a–e) were readily prepared by 6-chlorochromone and bulky 2,6-dimethylphenyl iso-
the aldol condensation of ortho-hydroxyacetophe- cyanide do not react with maleimide (3c) under the
nones (7a–e) with dimethylformamide dimethyl acetal usual conditions (Table 3, entry 13); however, reflux-
(8) under microwave irradiation.[14] The reactions ing the reaction mixture for 6 h conveniently affords
were finished in just 2 min giving excellent yields of the desired xanthone (1t) in a moderate yield
virtually pure 9a–e, which could be directly used in (Table 3, entry 14).
the preparation of chromanones (5a–e; Table 2). Both
Importantly, in all cases the xanthones (1a–t) were
intermediates 9 and 5 crystallize from their respective cleanly isolated by crystallization, with no need for
reaction media, and hence, 2-oxo-2-(4-oxo-4H-chro- further purification.
men-3-yl)acetates (5a–e) could be easily and efficient-
In agreement with our initial prediction, the mecha-
ly obtained in two steps from commercially available nism of the reaction could be explained through
ortho-hydroxyacetophenones (7a–e), with no need for a [4+1] cycloaddition of the isocyanide (6) with the 3-
laborious purifications and in less than 30 min in the carbonylchromone (5) to give iminolactone inter-
overall process (Table 2).
Reactions of chomones 5a–e with N-phenylmale- which suffers a [4+2] cycloaddition with the dieno-
imide and isocyanides (6) have shown to be tolerant phile (3), leading to 7-oxabicyclo[2.2.1]heptane (2).
mediate (4’). This tautomerizes to aminofuran (4),
A
ACHTUNGTRENNUNG
to both electron-donor and electron-acceptor substitu- Then, the nitrogen lone pair assists the in situ opening
ents on the chromone (Table 3, entries 1–5). However, of the oxygen bridge and subsequent dehydration to
donor substituents as 7-methoxy (Table 3, entry 1) afford the aromatic 4-aminoxanthone 1 (Scheme 1).
and 6-methyl (Table 3, entry 3) have a beneficial
Multistep syntheses of aromatic amines[15] usually
effect on the reaction rate, considerably reducing the require the use of transition metals or strong acids or
time of the reaction, even when it was performed at bases for the dehydration or dehydrogenation of non-
room temperature. Conversely, the electron-with- aromatic intermediates in a synthetic step independ-
drawing group-containing 6-chlorochromone requires ent from the ring formation. In contrast, here all four
longer reaction times and higher temperatures steps, [4+1] cycloaddition, [4+2] cycloaddition,
(Table 3, entries 2 and 5). Unexpectedly, the reaction oxygen ring opening and aromatization, take place
with benzochromone 5e is more sluggish, and affords smoothly at room temperature in the same pot with
the corresponding pentacyclic aminoxanthone 1k in no need of catalysts.
only a 30% yield.
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Table 3. Scope of the reaction with different chromones, isocyanides and dienophiles.
Entry
R1
R2
R3
R4
X
Solvent
Temperature [8C]
Time [h]
Product (Yield [%])[a]
1
2
3
4
5
6
7
8
H
H
H
H
Cl
Me
OMe
H
H
H
H
H
OMe
H
OMe
H
OMe
H
c-C6H11
c-C6H11
c-C6H11
c-C6H11
t-Bu
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
PhCH2
NC6H5
NC6H5
NC6H5
NC6H5
NC6H5
NCH3
NCH3
O
O
NH
NH
NH
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
25
35
25
25
35
35
35
25
25
25
25
25
35
85
24
96
24
140
120
32
23
96
72
72
72
80
>200
6
1h (99)
1i (81)
1j (75)
1k (30)[b]
1l (85)
1m (94)
1n (81)
1o (83)
1p (87)
1q (86)
1r (30)
1s (70)
–
benzo
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
Me
Cl
Cl
9
10
11
12
13
14
t-Bu
2,6-Me2C6H3
2,6-Me2C6H3
H
H
NH
NH
1t (53)[c]
[a]
General procedure: 1.1 equiv. of isocyanide and 1.1 equiv. of dienophile were added under nitrogen to a solution of
1equiv. of chromenone in THF.
Increasing the temperature to 358C or reflux decreased the reaction time but no improved yields were observed.
Reaction was carried out at THF reflux.
[b]
[c]
In summary, a high yielding and straightforward
solid obtained was recrystallized from toluene, heating in
the microwave reactor during 30 seconds at 1508C and then
cooling at 48C. The collected crystals were then washed
with hexane.
tandem synthesis of polysubstituted 4-aminoxan-
thones has been developed from readily accessible 3-
carbonylchromones, isocyanides and dienophiles. The
reaction is tolerant to a wide range of substituents on
the three starting materials, and takes place under
mild conditions with no need of catalysts. Importantly,
one new single and two new double carbon-carbon
bonds are formed in a simple synthetic operation. To
the best of our knowledge, this constitutes the first
multicomponent synthesis of xanthones reported up
to date.
Furthermore, a variety of starting chromones can
be readily prepared in a microwave-assisted two-step
procedure in less than 30 min. The overall three-step
process does not require any chromatographic purifi-
cation, as both the precursors and the final xanthones
can be cleanly isolated by crystallization from the re-
action media.
(E)-3-(Dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-
one (9a): Reaction time 2 min; yield: 89%, obtained as an
orange solid; mp 133–1378C (lit.[14] 1238C); IR: n=2920,
1628, 1548 cmÀ1 1H NMR (400 MHz, CDCl3): d=13.94 (s,
;
1H, OH), 7.89 (d, J=12.1 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H),
7.35 (t, J=8.5 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.81 (t, J=
8.1 Hz, 1H), 5.79 (d, J=12,1 Hz, 1H), 3.18 (s, 3H), 2.96 (s,
3H); 13C NMR (126 MHz, CDCl3): d=191.7 (C), 163.2 (C),
154.9 (CH), 134.1 (CH), 128.4 (CH), 120.5 (C), 118.4 (CH),
118.2 (CH), 90.3 (CH), 45.6 (CH3), 37.6 (CH3); MS (CI):
m/z (%)=220 (M+29, 79), 193 (M+, 92), 191 (100), 190
(35), 147 (90), 98 (100).
General Procedure for the Synthesis of Chromenones
(5a–5e)
A solution of methyl chlorooxoacetate (1.65 mmol) in 1,2-
dichloroethane (1 mL) was added dropwise to an ice-cooled
solution of enaminones 9a–9e (1.5 mmol) and pyridine
(3.3 mmol) in 1,2-dichloroethane (1 mL). The resulting mix-
ture was then stirred and irradiated (7–20 min) at 1008C in
a microwave device. The crude material was washed with
copper sulfate solution (to eliminate the pyridine) and
brine; the organic phase was dried with Na2SO4, filtered and
evaporated affording a solid, which was filtered and washed
with hexane.
Experimental Section
General Procedure for the Synthesis of Enaminones
(9a–9e)
A mixture of ortho-hydroxyacetophenone (10 mmol) and di-
methylformamide dimethyl acetal (10 mmol) was stirred and
irradiated (1–2 min) at 1508C in a microwave device. The
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COMMUNICATIONS
Ana Bornadiego et al.
Methyl 2-oxo-2-(4-oxo-4H-chromen-3-yl)acetate (5a): Re-
action time: 7 min; yield: 85%, obtained as a bright brown
solid; mp 131–1358C (lit.[13] 133–1358C); IR: n=3063, 2955,
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1
1731, 1694, 1649 cmÀ1; H NMR (500 MHz, CDCl3): d=8.66
(s, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.77 (t, J=8.5 Hz, 1H),
7.56 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.5, 1H), 4.00 (s, 3H);
13C NMR (126 MHz, CDCl3): d=184.7 (C), 174.8 (C), 164.4
(C), 162.4 (CH), 156.3 (C), 135.2 (CH), 127.1 (CH) 126.5
(CH), 124.9 (C), 120.1 (C), 118.8 (CH), 53.2 (CH3); MS
(CI): m/z (%)=261 (M+29, 22), 234 (M+2, 85), 233 (M+
1, 98), 232 (M+, 99), 217 (69), 121 (22).
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General Procedure for the Synthesis of 4-
Aminoxanthones
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To a solution of chromenone 5a–5e (0.3 mmol) in dry THF
(2 mL), isocyanide 6a–6g (0.36 mmol) and dienophile 3a–3d
(0.36 mmol) were successively added. The resulting mixture
was stirred at room temperature or 358C under a nitrogen
atmosphere until all the starting chromone had been con-
sumed, as judged by TLC. HCl (1N) was added to the reac-
tion mixture, the organic phase was extracted with CH2Cl2,
dried (Na2SO4) and concentrated. The resulting solid was fil-
tered and washed with hexane, giving the desired product
1a–1t.
Methyl
4-(cyclohexylamino)-1,3,10-trioxo-2-phenyl-
[2,3-f]isoindole-11-carboxylate
1,2,3,10-tetrahydrochromenoAHCNUTGTRENNUNG
(1a): Reaction temperature: 358C; reaction time: 96 h;
yield: 99%, obtained as a yellow solid; mp 250–2538C
(dec.); IR: n=3331, 2942, 2842, 1758, 1702, 1661 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=8.31 (d, J=7.9 Hz, 1H),
7.82 (t, J=8.6 Hz, 1H) 7.51–7.34 (m, 9H), 6.95 (s, 1H), 4.44
(m, 1H), 4.11 (s, 3H), 2.17–1.15 (m, 10H); 13C NMR
(101 MHz, CDCl3): d=175.9 (C), 168.2 (C), 167.2 (C), 164.7
(C), 155.1 (C), 149.3 (C), 139.1 (C), 135.9 (CH), 131.4 (C),
129.3 (CH), 128.4 (CH), 127.2 (CH), 126.6 (CH), 125.8
(CH), 123.3 (C), 123.0 (C), 121.6 (C), 118.3 (C), 117.9 (CH),
112.2 (C), 54.5 (CH), 53.5 (CH3), 34.9 (CH2), 25.6 (CH2),
24.8 (CH2); MS (EI): m/z (%)=497 (M+,20), 496 (M, 62),
453 (92), 421 (35), 383 (52); HR-MS (EI): m/z=496.1626,
calcd. for C29H24N2O6: 496.1634.
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